Biology subjects

Anouar, Y.

Publications and source records attributed to Anouar, Y..

5 recordsLinked to original sources

bioRxiv2023

Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells

Non-small cell lung cancers (NSCLCs) treated with tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) almost invariably relapse in the long term, due to the emergence of subpopulations of resistant cells. Here we show that the lack of sensitivity of these cells to EGFR-TKIs constitutes a vulnerability that can be potentially targeted. Through a DNA barcoding approach, we demonstrate that the clinically approved drug sorafenib specifically abolishes the selective advantage of EGFR-TKI-resistant cells, while preserving the response of EGFR-TKI-sensitive cells, thus resulting in overall inhibition of clonal evolution within the tumor cell mass population. Sorafenib is active against multiple mechanisms of resistance/tolerance to EGFR-TKIs and its effects depend on early inhibition of MAPK interacting kinase (MNK) activity and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and later down-regulation of MCL1 and EGFR. Using several xenograft and allograft models to recapitulate different mechanisms and kinetics of acquired resistance, we show that the sorafenib-EGFR-TKI combination can substantially delay tumor growth and promote the recruitment of inflammatory cells. Together, our findings indicate that sorafenib can substantially prolong the response to EGFR-TKIs by targeting NSCLC capacity to adapt to treatment through the emergence of resistant cells.

cancer biology↗

bioRxiv2021

SELENOT deficiency alters projection neuron migration during corticogenesis in mice

During corticogenesis, projection neurons migrate along the radial glial axis to form cortical layers, the alteration of which is associated with functional deficits in adulthood. As byproducts of cell metabolism, reactive oxygen species act as second messengers to contribute to neurodevelopment; however, free radical excess may impede this process. SELENOT is a thioredoxin-like enzyme of the endoplasmic reticulum abundantly expressed during embryogenesis whose gene disruption in the brain leads to neuroblast cell demise due to increased free radical levels. To determine the potential contribution of SELENOT to the establishment of cortical networks, we analyzed first its expression profile in the neocortex at different stages of development. These studies revealed the widespread expression of SELENOT in all cortical layers, and its continous increase throughout mouse lifespan. In addition, we disrupted the SELENOT gene in the cortex using in utero electroporation and Nes-Cre/lox knockout. SELENOT deficiency altered neuroblast migration polarity, at the level of radial scaffolding, and projection neuron positionning. These results indicate that SELENOT plays a crucial role during neurodevelopment by sustaining projection neuron migration.

developmental biology↗

bioRxiv2021

Identification of a discrete neuronal circuit that relays insulin signaling into the brain to regulate glucose homeostasis

26RFa (QRFP) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localized in the hypothalamus. In the present study, we have investigated whether the 26RFa neurons may be involved in the hypothalamic regulation of glucose homeostasis. Our data indicate that 26RFa, i.c.v. injected, induces a robust antihyperglycemic effect associated with an increase of insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26RFa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26RFa in the lateral hypothalamic area and the ventromedial hypothalamic nucleus also express the insulin receptor and that insulin induces the expression of 26RFa in these neurons. Concurrently, we show that the central antihyperglycemic effect of insulin is abolished in presence of a 26RFa receptor (GPR103) antagonist as well as in mice deficient for 26RFa. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production. To conclude, in the present study we have identified a novel actor of the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system and we provide the evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.

physiology↗

bioRxiv2019

Glucose homeostasis is impaired in mice deficient for the neuropeptide 26RFa (QRFP)

Introduction26RFa (QRFP) is a biologically active peptide that has been found to control feeding behaviour by stimulating food intake, and to regulate glucose homeostasis by acting as an incretin. The aim of the present study was thus to investigate the impact of 26RFa gene knockout on the regulation of energy and glucose metabolism. Research design and methods26RFa mutant mice were generated by homologous recombination, in which the entire coding region of prepro-26RFa was replaced by the iCre sequence. Energy and glucose metabolism was evaluated through measurement of complementary parameters. Morphological and physiological alterations of the pancreatic islets were also investigated. ResultsOur data do not reveal significant alteration of energy metabolism in the 26RFa-deficient mice except the occurrence of an increased basal metabolic rate. By contrast, 26RFa mutant mice exhibit an altered glycemic phenotype with an increased hyperglycemia after a glucose challenge associated with an impaired insulin production, and an elevated hepatic glucose production. 2D and 3D immunohistochemical experiments indicate that the insulin content of pancreatic {beta} cells is much lower in the 26RFa-/- mice as compared to the wild-type littermates. ConclusionDisruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis with, in particular, a deficit in insulin production by the pancreatic islets. These findings further support the notion that 26RFa is an important regulator of glucose homeostasis. Significance of this studyO_ST_ABSWhat is already known about this subject?C_ST_ABS26RFa is a biologically active peptide produced in abundance in the gut and the pancreas. 26RFa has been found to regulate glucose homeostasis by acting as an incretin and by increasing insulin sensitivity. What are the new findings?Disruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis with, in particular, a deficit in insulin production by the pancreatic islets, assessing therefore the notion that 26RFa is an important regulator of glucose homeostasis. How might these results change the focus of research or clinical practice?Identification of a novel actor in the regulation of glucose homeostasis is crucial to better understand the general control of glucose metabolism in physiological and pathophysiological conditions, and opens new fields of investigation to develop innovative drugs to treat diabetes mellitus.

physiology↗

bioRxiv2017

Improving bioinformatics prediction of microRNA targets by ranks aggregation

microRNAs are non-coding RNAs which down-regulate a large number of target mRNAs and modulate cell activity. Despite continued progress, bioinformatics prediction of microRNA targets remains a challenge since available softwares still suffer from a lack of accuracy and sensitivity. Moreover, these tools show fairly inconsistent results from one another. Thus, in an attempt to circumvent these difficulties, we aggregated all human results of three important prediction algorithms (miRanda, PITA and SVmicrO) showing additional characteristics in order to rerank them into a single list. This database is freely available through a webtool called miRabel (http://bioinfo.univ-rouen.fr/mirabel/) which can take either a list of miRNAs, genes or signaling pathways as search inputs. Receiver Operating Characteristic curves and Precision-Recall curves analysis carried out using experimentally validated data and very large datasets show that miRabel significantly improves the prediction of miRNA targets compared to the three algorithms used separatly. Moreover, using the same analytical methods, miRabel shows significantly better predictions than other popular algorithms such as MBSTAR and miRWalk. Interestingly, a F-score analysis revealed that miRabel also significantly improves the relevance of the top results. The aggregation of results from different databases is therefore a powerful and generalizable approach to many other species to improve miRNA target predictions. Thus, miRabel is an efficient tool to accurately identify miRNA targets and integrate them into a biological context.

bioinformatics↗